The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder

Quist, Jennifer; Barr, Cathy L.; Schachar, Russell; Roberts, Wendy; Malone, Molly; Tannock, Rosemary; Basile, Vincenzo S.; Beitchman, Joseph H.; Kennedy, James L.

doi:10.1038/sj.mp.4001244

Cited by 118 publications

(70 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given previous findings of preferential paternal transmission bias with other candidate genes in ADHD, [23][24][25][26] TDTPHASE 27 was used to test transmissions from fathers and mothers separately. The proportions of transmitted vs nontransmitted alleles between ADHD subtypes and comorbid groups were compared using w 2 tests.…”

Section: Methodsmentioning

confidence: 99%

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

et al. 2005

View full text Add to dashboard Cite

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR ¼ 1.6, P ¼ 0.02) with a strong paternal effect (paternal transmissions: OR ¼ 3.2, P ¼ 0.0005; maternal transmissions: OR ¼ 1.00; P ¼ 1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved. Keywords: attention deficit hyperactivity disorder; association study; neurotrophic factor; polymorphism Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2-5% of school-aged children with more boys diagnosed than girls. 1 It is characterized by marked and pervasive inattention, overactivity and impulsiveness and causes significant social, educational and psychological problems. Quantitative genetic research over the last decade, from family, twin and adoption studies has firmly established that ADHD has a significant genetic contribution. 2 The medications most often used for ADHD are psychostimulants including methylphenidate and dexamphetamine. Precise therapeutic mechanisms of these drugs in ADHD remain unclear, although methylphenidate is known to inhibit the dopamine transporter. As a result, most candidate gene studies to date have focused on the dopamine system. 3 Positive findings have been successfully replicated for variants in the D4 dopamine receptor (DRD4), 4 D5 dopamine receptor (DRD5) 5 and the dopamine transporter (DAT1). 6 These family-based meta-analyses each report small effect sizes with odds ratios of less than 1.5, indicating that if they are true susceptibility variants for ADHD their contribution to the overall phenotype is small. Given that ADHD is a neurodevelopmental disorder, genes involved in neuronal development and growth represent an important set of candidates for involvement in the pathogenesis. One such candidate that has been postulated to play a role in ADHD is BDNF (MIM 113505). 7 The gene encoding BDNF is located at 11p13 and codes for a precursor peptide (proBDNF), which is proteolytically cleaved to form the mature protein. Only one nonsynonymous polymorphism in the human BDNF gene (rs 6265) has been identified, a single nucleotide polymorph...

show abstract

Section: Methodsmentioning

confidence: 99%

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

et al. 2005

View full text Add to dashboard Cite

show abstract

“…In particular, replicated associations have been reported with the dopamine D4 and D5 receptors (DRD4 and DRD5), 4,[11][12][13] the dopamine transporter (DAT1) and the serotonin 1B receptor (5HT1B) 14,15 genes. Although the identification of such consistent findings is unusual in the study of human behavioural disorders, uncertainties remain over their validity and further evidence is required before we can be confident that the reported findings represent true genetic associations.…”

Section: Introductionmentioning

confidence: 92%

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Chen

Mill

et al. 2003

Mol Psychiatry

View full text Add to dashboard Cite

Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3 0 -UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (v 2 ¼ 10.8, 1 d.f., p ¼ 0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.

show abstract

“…In particular, the changes in 5-HT1A receptor expression are considered an important determinant of predisposition to mental illness 33 and, although the mechanisms underlying the variable expression of this locus between individuals remain unclear, transcriptional dysregulation has been suggested as a probable candidate 34 . 5-HT2A and 5-HT1B receptors are also of great relevance for behavioural disorders 35,36 . These three 5-HT receptors are particularly abundant in corticolimbic regions targeted for H2BGFP expression in bitransgenic animals.…”

Section: Discussionmentioning

confidence: 99%

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

et al. 2014

View full text Add to dashboard Cite

The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture.

show abstract

The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder

Cited by 118 publications

References 26 publications

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

Contact Info

Product

Resources

About